To elucidate the role of the beta-sympathetic system in thyrotoxicosis (THY), we examined cardiac sensitivity to infused beta-agonist and compared the effect of beta-blockade with that of resolution of the hyperthyroid state. Beta-sympathetic (beta-SYM) sensitivity was measured as the heart rate response to isoproterenol in THY patients and in normal subjects. The patients with THY showed both lower threshold (P less than 0.05) and increased slope (P less than 0.05) of the heart rate-isoproterenol response, suggesting beta-SYM hypersensitivity. The beta-SYM like features of THY were measured in 7 patients before and 7 days after beta-SYM blockade with propranolol (mean dose 411 +/- 32 mg/day [SEM]) which was shown to block the heart rate response to isoproterenol. These results were compared with those in a similar group of thyrotoxic patients rendered euthyroid with 131I. During beta-SYM blockade, heart rate decreased from 101 +/- 6.3 to 78 +/- 4.6 (P less than 0.01), but the elevated metabolic rate (V02), resting ventilation (VE), and increased hypoxic and hypercapnic ventilatory responses were not significantly affected. In the group rendered euthyroid with 131I, heart rate decreased from 110 +/- 3.5 to 76 +/- 7.8 (P less than 0.02), but in contrast to the result of beta-SYM blockade, a 28% decrease in VO2 (P less than 0.01), 41% decrease in VE (P less than 0.05), a 38% decrease in hypercapnic ventilatory response (P less than 0.05), and a 66% decrease in hypoxic response (P less than 0.03) occurred. During THY, beta-SYM mechanisms are responsible for part of the tachycardia, but the metabolic and ventilatory abnormalities are not beta-SYM mediated.